Substituted glycinamide



Patented May 18, 1954 UNITED stares tartar OFFICE SUBSTITUTED GLYCINAMIDE William F. Bruce, Delaware County, and Joseph Seifter, Montgomery County, Pa., assignors, by mesne assignments, to American Home Products Corporation, New York, N. 1., a corporation of Delaware 1 Claim.

This invention relates to new substituted gly- .cinamides, and more particularly relates to gly- :cinamides having the general formula where R1 and R2 both represent aralkyl radicals and where R1 stands for an aralkyl having an alkyl chain of l carbon atoms.

The compounds disclosed herein which have been found to be particularly useful are branched arallryl glycinamides or acetamides wherein the amino or left-hand portion of the acetamide molecule has a branched-alkyl chain of four carbon atoms as indicated.

The compounds of the type involved here are useful as intermediates in the formation of other amides and in the preparation of desirable quaternary ammonium compounds. Other, and it is believed, more important uses have been pointed out specifically in our prior application Serial No.

358, filed January 2, 194$, now Patent No. 2,499,-

352, these uses involving the discovery that certain glycinamides have valuable pharmacological action showing at least one of the following actions: local anesthetic, pressor, spasmolytio, an-

algesic, sedative and convulsant action.

It is further contemplated that when R1 and R2 represent the radicals indicated above, one or more of the hydrogen atoms on the allzyl chain or on a ring may be replaced by a hydroxy or alkoxy group.

In general, the compounds of the invention may be synthesized by reacting an appropriate chloroacetamide corresponding to the formula ClCHzCONHRz with an appropriate primary amine corresponding to the formula R1NI-Iz where R1 and R2 have the same meaning as indicated hereinabove.

The primary amine may be prepared in known manner. The preferred method for preparation of the chloroacetamide intermediate involves reacting chloroacetylchloride with a primary amine R2NH2 in the presence of benzene as a solvent for the reactants. Heating may or may not be necessary depending on the speed of the particular reaction. The chloroacetamide remains in solution and is separated from the solvent by distilling off the latter under low pressures. In general, a molar ratio of chloride to amine of about 1:2 is preferred for the reaction.

The reaction of the appropriate chloroacetamide and the appropriate primary amine to form the desired substituted glycinamide is preferably operated with a molar ratio, amide to amine of about 1:1 and is carried out in the presence of a solvent for the reactants such as higher alcohols having four to seven carbon atoms in the molecule, dioxane or hydrocarbon solvents, for example, xylene. The reaction is carried out also in the presence of an acid acceptor or mildly basic material such as alkali or alkaline earth metal carbonates, sodium bicarbonate or alkali metal alcoholates, and preferably about 2 to 3 mols. of this material is used. The reaction operation is set up for refluxing and the temperature is the refluxing temperature of the particular solvent selected. Generally a period of about l0-l5 hours is suflicient for complete reaction. In the event that solids are formed, these are removed by filtration, the product remaining in solution in the solvent. The solvent is then removed by distillation at 10V pressures to obtain the sub stituted glycinamide product.

It is known that certain amines possess a vasoconstrictor action and are identified as pressor amines. As an important feature of the invention, it has been discovered that when pressor amines, represented by the above-mentioned RiNl-lz or R2NH2 amines, are used as intermediates in forming the new compounds, and particularly when R1NH2 is a pressor amine, the new products possess pronounced physiological action. When both amines are pressor amines, even greater physiological action in the new compounds has been noted. Thus in substituted glycinamides corresponding to the formula RiNHCHzCONHRz when a pressor amine has been combined, and particularly on the amino side (left-hand side) of the molecule, the compounds possess very con siderable anesthetic action and in some cases anesthetic action of a high order combined with pressor action. While certain pressor amines may themselves possess a certain small amount of local anesthetic action, a surprising increase in anesthetic action has been found in the corresponding glycinamide compounds.

Certain of the compounds of the invention have been found also to possess not only a local anesthetic action superior to cocaine, but also a spasmolytic or anti-spasmodic action, while at the same time having a toxicity considerably below that of cocaine.

Proceeding to a better understanding of this invention, an illustrative specific procedure for the preparation of representative compounds falling within the general formula is set forth in the following examples.

EXAMPLE I Preparation of omega-phenyl-terL-butylamino- N diphenylmethyl acetamide To 450 cc. of n-butyl alcohol contained in a one liter 3-neck fiask, fitted with a mechanical stirrer, reflux condenser and a thermometer was added g. of omega-phenyl-tert.-butylamine, g. of chloro-N-diphenylmethyl acetamide and g. of sodium carbonate. The reaction mixture was heated at 100 C. overnight. It was filtered hot to remove the inorganic salts. The salts were washed with n-butyl alcohol and the washings added to the filtrate. The latter was washed. with sodium carbonate solution until no halogen could be detected by the Beilstein test. The filtrate was dried over magnesium sulfate and the alcohol distilled off under vacuum. The. product was fractionated. B. P. 160-165 C. at 0.4 mm.

In the same way, chloro-Ndipheny1methyl cetamide may be reacted with 1,1-dimethyl-2- hydroxy-2-phenylethylamine, using the same molar ratios, to form alpha-1,1-dimethyl-2-hy droxy 2 phenylethylamino N diphenylmethyl acetamide.

EXAMPLE II Preparation of omega-phenyl-tcrt.-butylamino- N-omega-phenyl-tert.-butyl acetamide To 500 cc. of n-butyl alcohol contained in a one liter B-neck flask fitted with a mechanical stirrer. reflux condenser and a thermometer was added 10 g. of omega-phenyl-tert.-butylamine, 15 g. of chloroll-omega-phenyl-tert.buty1 acetamide and g. of sodium carbonate. The reaction mixture was heated at C. overnight. The reaction mixture was filtered hot to remove the inorganic salt formed. The salts were washed with n-butyl alcohol and the washings added to the filtrate. This was washed with sodium carbonate solution until no halogen could be detected by the Beilstein test. The filtrate was then dried over magnesium sulfate and the alcohol distilled oif under vacuum. The product was fractionated. B. P. 200-204 C. at 0.5 mm.

EXAMPLEIII Preparation of alpha-is0propyZbeneyZamino-N- aZpha-zsoprcpylbeneyl acetamide A mixture of 0.2 mol. isobutyrophenone and 0.5 mol. of ammonia is shaken with 0.3 g. of platinum oxide to give 0.1 mol. of phenylisopropylcarbinamine. This is treated with 0.1 mol. of

chloroacetylchloride to give 0.1 mol. of chloroacetophenylisopropyl carbinamine. The latter is then condensed with phenylisopropyl carbinamine to give 007 mol. of the glycinamide.

In the manner taught by the examples, using the same molar ratios, one may react 0.1 mol. of chloroacetylchloride with 0.1 mol. of 1-methyl-2- phenylethylamine to give chloro-N-l-methyl-Z- phenylethyl acetamide. The latter may then be reacted with omega-phenyl-tert.-butylamine to give alpha-1,1-dimethyl-2-phenylethylamino-N- l-methyl-Z-phenylethyl acetamide.

Substantially all of the products of the invention are high boiling basic liquids of limited solubility. It is contemplated within the scope of this invention that while the products may be used in their basic form, they may also be prepared and used in the well-known manner in the form of their acid-addition salts. The preparation of such a salt is well-known and generally involves the addition of the selected acid to an ether, alcohol or water solution of the basic product. The acid is chosen to yield a salt which is known to those skilled in the art as being physiologically non-toxic. As examples, the hydrochloride, sulfate or acetate salts of the new products may be used.

It is further contemplated that those substituted glycinamides, or the non-toxic salts thereof, which are less soluble in dilute acid than 0.5% by weight, may be brought into satisfactory solution by the use of solubilizing, surface-active, emulsifying or detergent agents in order to obtain a more complete physiological efiect of the specific substituted glycinamide. Lipoid solvents having a physiologically non-toxic effect such as long chain fatty acid partial esters of hexitol anhydrides or oxyalkylene derivatives thereof, vegetable and animal oils and ointment bases such as petroleum jelly or cholesterol are examples of solvents that are considered useful in admixture with the substituted glycinamides for obtaining an enhanced physiological effect.

We claim:

The new compound, alpha-N-(Ll-dimethyl-Z- phenylethylamino) -N-diphenylmethyl acetamide.

References Cited in the file of this patent UNITED STATES PATENTS Number Name Date 2,449,638 Bruce Sept. 21, 1948 2,499,352 Bruce Mar. 7, 1950 

